The asymptomatic nature of OVCA together with lack of effective diagnostic screening tools makes the disease extremely difficult to detect at an early stage. Consequently, OVCA is often diagnosed at an advanced stage in approximately 70% of patients (1). Despite an initial response to primary, or “first-line”, treatment more than 85% of patients with advanced disease will experience OVCA recurrence after the completion of first-line treatment even with optimal surgical cytoreduction and platinum-based combination chemotherapy (2,3). Patients bearing platinum-sensitive tumors have a relapse-free period of at least 6 months following their last platinum treatment compared to patients bearing platinum resistant tumors who fail to achieve complete response after first-line treatment and relapse in less than 6 months from the completion of therapy (4). Evaluation of effects of primary treatment and the early detection of recurrence in those with platinum-sensitive tumors is an important goal of routine follow-up to improve the life expectancy.
Over the years CA125 has emerged as a useful biomarker for monitoring of OVCA recurrence (5). To date, CA125 is most extensively used in monitoring OVCA during routine follow-up visits because in about 80% of patients an increase in the level of CA125 may be the first indication of relapse that precedes recurrence by 3-5 months (30). Redman and colleagues (6) reported that after two courses of chemotherapy, OVCA patients with CA125 values less than 35 U/ml were more likely to achieve remission of disease with longer median survival. Their analyses revealed that the level of CA125 after two courses of chemotherapy treatment appeared as an independent prognostic factor because it predicted the survival status at 12 months with an overall accuracy of 93%. In another study, level of CA125 was found to be elevated above the normal range in 73% of relapsed patients. In that study, physical and gynecological examinations in combination with CA125 increased the detection of relapse up to 92% (7). The study conducted by Krivak and colleagues (8) indicated that following surgery and 6 cycles of chemotherapy, OVCA patients with persistently abnormal CA125 levels >35 U/ml were 2.45 times more likely to have a disease progression (95% CI: 1.52-3.95, P<0.001) and the risk of death for those patients was more than 2.78 times (95% CI: 1.66-4.65, P<0.001) than those with CA125 less than 35 U/ml. Several studies evaluated the risk of recurrence in epithelial OVCA patients with rising CA125 values below the upper limit of normal (<35 U/ml). Wilder and colleagues (9) reported that OVCA patients who had three progressively rising CA125 levels within a normal range (<35 U/ml) at 1-3 months follow-up intervals were associated with a high risk of tumor recurrence. Eleven out of 100 patients who achieved complete remission after surgery and chemotherapy met the criteria for inclusion in their study and were followed at 1 to 3 month intervals with serial CA125 determinations. All 11 patients developed recurrent cancer within 12-33 months after completion of primary treatment. The recent report from a MRC/EORTC (Medical Research Council/European Organisation for Research and Treatment of Cancer) trial demonstrated that OVCA patients with a rising CA125 who received chemotherapy treatments prior to the appearance of clinical symptoms of recurrence had no mortality benefit (31). The limitation of their study was that it took a long time for them to enroll patients and as a result clinician bias may have been introduced for not registering patients who were considered likely to benefit from early chemotherapy. Furthermore, the lack of a benefit in early treatment has been argued to be a result of enrolling patients with poor prognoses (42).
Although CA125 is the most extensively investigated biomarker for diagnosis and monitoring of OVCA, a variety of other tumor biomarkers have been reported to be useful for monitoring response to therapy or indicating relapse during follow-up visits. Anastasi and colleagues conducted a follow-up retrospective study for survival analysis of 8/32 patients with advanced OVCA by evaluating the levels of human epididymis protein 4 (HE4) and CA125 in the serum samples that were collected at the time of diagnosis and at intervals during 16-20 months after surgery. Their study showed that 5/8 patients had an increase in HE4 level above the cut-off value that preceded the rise of CA125 by 5-8 months. This early increase in HE4 level was associated with the relapse of the disease (10). Another study showed that the level of Osteopontin (OPN), a putative plasma biomarker, increased earlier than CA125 in 90% of the patients developing progressive or recurrent epithelial OVCA (median lead time, 3 months) although its role in predicting clinical response to therapy was considered inferior to CA125 (11). Tassi and colleagues (12) reported significant elevation in the expression of Mammaglobin B (MGB-2), a secretoglobin family member, in epithelial OVCA. Univariate survival analysis on 106 OVCA patients enrolled in their study revealed significant correlation of MGB-2 expression with reduced risks of cancer-related death, recurrence and disease progression (p<0.05). In another study, the utility of a biomarker panel comprised of HE4, MMP7 and Glycodelin was evaluated to predict recurrence in a longitudinal monitoring cohort of 30 patients with advanced OVCA. The results indicated that in 27/30 patients who experienced recurrence following initial response to chemotherapy, this biomarker panel predicted recurrence with a sensitivity of 100% compared to 96% for CA125 alone. In 56% patients, the level of one or more panel biomarkers was elevated 6-69 weeks before the rise in CA125 and prior to other clinical evidence of recurrence (13). Other studies examined the BRCAness profile of sporadic ovarian carcinomas in late stage OVCA patients in which the majority had poorly differentiated grade 3 cancers and serous histology. One such study indicated that 41% (7/17) patients who recurred within first year of diagnosis, had tumors with high expression of PARP, FANCD2 and p53 proteins compared to 19% (29/149) patients in the non-recurrence group whose tumors had low expression of the above 3 proteins (14).
Tumor autoantibodies develop at very early stage, well before the clinical manifestations of the disease because of the activation of humoral immune responses due to the presence of small amounts of tumor associated antigens (TAAs) even at very low tumor burden (15). Thus, antibodies against tumor specific proteins may provide the earliest candidate biomarkers for detecting OVCA as well as for monitoring OVCA during the first-line chemotherapy that will provide a signal for the risk of developing OVCA recurrence.
There is a need for reagents that sensitively and specifically detect autoantibody biomarkers associated with ovarian cancer recurrence, and for methods of using these reagents to predict the recurrence of ovarian cancer. There is also a need for methods of directing OVCA treatment selectively toward patients at risk of recurrence.